Apolipoprotein M promoter polymorphisms alter promoter activity and confer the susceptibility to the development of type 1 diabetes

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5 Dongdan 3 Tiao, Beijing 100005, PR China.
Clinical biochemistry (Impact Factor: 2.28). 11/2008; 42(1-2):17-21. DOI: 10.1016/j.clinbiochem.2008.10.008
Source: PubMed


Apolipoprotein M plays an important role in the formation of prebeta-HDL and cholesterol efflux to HDL. In the present study, we investigate the potential association between the ApoM promoter polymorphisms and type 1 diabetes.
The study was conducted in Peking Union Medical College, Beijing, China and Karolinska Institutet, Stockholm, Sweden. Two populations, including 493 Han Chinese subjects (177 T1D patients/316 controls) and 225 Swedish (124/101), are enrolled in the present study. Three single nucleotide polymorphisms (SNP) C-1065A, T-855C and T-778C in the promoter region of the ApoM gene are genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Promoter activity was measured by reporter gene assay.
SNP T-778C was strongly associated with T1D in both Han Chinese (p=0.002, OR=2.188, CI 95%=1.338-3.581) and Swedish (p=0.021, OR=2.865, CI 95%=1.128-7.278) populations. The luciferase activity of -778C promoter was 1.41 times as high as that of -778T promoter (9.90+/-1.92 vs. 7.04+/-0.76, p=0.001).
Allele C of SNP T-778C may increase promoter activity and confer the risk susceptibility to the development of T1D.

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    • "The rs805297 SNP site is localized to the promoter, which may affect gene transcription and concomitant protein levels in the blood to underlie its disease association. This hypothesis is supported by previous literature indicating that the C allele of rs805296 SNP may increase promoter activity and confer the risk susceptibility to type I diabetes [16]. Additionally, Hae-Jin Hu and colleagues suggested that rs805297 polymorphism in the apoM promoter may decrease its transcriptional activity and thus alter HDL-C concentrations to ultimately affect RA susceptibility [17]. "
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    ABSTRACT: Backgrounds: It has been reported that rs940494 and rs805296 SNPs of apolipoprotein M (apoM) gene may confer the risk in the development of type 2 diabetes (T2D) and coronary artery disease (CAD) in the Han Chinese. However, a recent study demonstrated that rs805297 polymorphism is significantly associated with reduced total high density lipoprotein (HDL) levels in rheumatoid arthritis patients. But the relationship between rs805297 SNP and CAD has not been explored. The aim of the present study was to elucidate whether the rs805297 mutant allele is implicated in CAD and links to changes in blood lipid levels in these patients. Three hundred CAD patients and three hundred and twelve non-CAD patients were subjected in the present study. All subjects were confirmed by the angiography. Plasma concentrations of apoM were semi-quantitatively determined by dot-blotting analysis, and total serum lipid levels were quantified using an automated RA-1000 (Technician, USA). The genotyping of rs805297 of apoM was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotype and allele frequencies were not significant (P=0.5798 and 0.3834, respectively) between cases and controls. Compared with the wild-type C/C genotype, carriers of the C/A and A/A genotypes did not have an increased risk of CAD, as determined by multiple logistic regression analysis, after adjustment for age, sex, BMI, history of smoking, hypertension and hypercholesterolemia. (CA, odds ratio = 0.49, 95% confidence interval 0.15-1.87, P = 0.462; AA, odds ratio = 0.51, 95% confidence interval 0.13-1.68, P = 0.534). The plasma concentration levels of apoM did not differ significantly among carriers of the three genotypes between two groups. Lastly, control subjects with A/A genotypes had lower total levels of HDL cholesterol than did those with C/C genotypes. The results presented here suggest that the rs805297 SNP is not associated with an increased risk of developing CAD, although it does independently correlate with dyslipidaemia in Han Chinese individuals.
    Lipids in Health and Disease 12/2013; 12(1):184. DOI:10.1186/1476-511X-12-184 · 2.22 Impact Factor
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    • "Ten studies [14-23], 5 in English [15,18,20-22] and 5 in Chinese [14,16,17,19,23] met the included criteria for this meta-analysis (Figure 1). All of the studies had been approved by the Ethics Committee of their affiliations, in accordance with the Helsinki Declaration of 1975 as revised in 1983, and all subjects had given informed consent. "
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    ABSTRACT: The apolipoprotein M (APOM) T-778C gene polymorphism has been associated with serum lipid levels and the risk of coronary artery disease (CAD), but the results are inconclusive. The purpose of this meta-analysis was to detect the association between the APOM T-778C polymorphism and serum lipid levels and the risk of CAD in the Chinese population. Databases of MEDLINE, EMBASE, the Cochrane Library and CNKI were systematically searched. Data were extracted using standardized methods. The association was assessed by mean difference (MD) with 95% confidence intervals (CI) or odds ratio (OR) with 95% CI. Ten studies with 4,413 patients were included in this meta-analysis. Pooled effects indicated that CT+CC group had higher levels of total cholesterol (TC) (MD:-0.36, 95% CI: -0.53 -- -0.19, P < 0.0001) and low-density lipoprotein cholesterol (LDL-C) (MD: -0.08, 95% CI: -0.16 -- -0.01, P = 0.03) than TT group. There was no difference in the levels of triglyceride (MD: 0.06, 95% CI: -0.04 -- 0.15, P = 0.22) and high-density lipoprotein cholesterol (MD: 0.00, 95% CI: -0.03--0.03, P = 0.93) between TT and CT+CC groups. Pooled effects showed that CAD group had higher CT+CC genotype frequency than control group (OR: 1.97, 95% CI: 1.62--2.39, P < 0.00001; heterogeneity test x2 = 2.96, P = 0.71, I2 = 0%). The results of the current meta-analysis show that the CT+CC group has higher levels of TC and LDL-C than the TT group. Moreover, there is also a prominent association between APOM T-778C polymorphism and the risk of CAD in the Chinese population, the CT+CC genotype is associated with increased risk of CAD.
    Lipids in Health and Disease 09/2013; 12(1):135. DOI:10.1186/1476-511X-12-135 · 2.22 Impact Factor
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    • "A SNP (rs805296) located in APOM promoter region near rs805297 was also found to be significantly associated with RA. SNP rs805296 has been implicated in some diseases such as coronary artery disease and type 1 diabetes mellitus (T1DM), but not in RA (Jiao et al., 2007; Wu et al., 2009). Given that T1DM is an autoimmune disease and that there is a higher risk of atherosclerosis in RA patients than normal individuals, we could assume that APOM promoter polymorphism SNP rs805296 may also be involved in both autoimmune mediated-and inflammation mediated-diseases. "
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    ABSTRACT: Although the genetic component in the etiology of rheumatoid arthritis (RA) has been consistently suggested, many novel genetic loci remain to uncover. To identify RA risk loci, we performed a genome-wide association study (GWAS) with 100 RA cases and 600 controls using Affymetrix SNP array 5.0. The candidate risk locus (APOM gene) was re-sequenced to discover novel promoter and coding variants in a group of the subjects. Replication was performed with the independent case-control set comprising of 578 RAs and 711 controls. Through GWAS, we identified a novel SNP associated with RA at the APOM gene in the MHC class III region on 6p21.33 (rs805297, odds ratio (OR) = 2.28, P = 5.20 × 10-7). Three more polymorphisms were identified at the promoter region of the APOM by the re-sequencing. For the replication, we genotyped the four SNP loci in the independent case-control set. The association of rs805297 identified by GWAS was successfully replicated (OR = 1.40, P = 6.65 × 10-5). The association became more significant in the combined analysis of discovery and replication sets (OR = 1.56, P = 2.73 × 10-10). The individuals with the rs805297 risk allele (A) at the promoter region showed a significantly lower level of APOM expression compared with those with the protective allele (C) homozygote. In the logistic regressions by the phenotype status, the homozygote risk genotype (A/A) consistently showed higher ORs than the heterozygote one (A/C) for the phenotype-positive RAs. These results indicate that APOM promoter polymorphisms are significantly associated with the susceptibility to RA.
    Experimental and Molecular Medicine 08/2011; 43(11):613-21. DOI:10.3858/emm.2011.43.11.068 · 3.45 Impact Factor
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